tbuckley/cabot-search huggingface dataset:
Xenonucleic acid technology in high-sensitivity IDH1/2 mutation detection for glioma molecular profiling.
Authors: Hongjun Yang, Herui Wang, Xueyu Sang, Zhengping Zhuang, Andrew Y. Fu, Michael Sha
Journal: Journal of Clinical Oncology (2023)

e14052 Background: Glioma is a life-threatening primary brain tumor that poses significant challenges for diagnosis and treatment. Certain genetic features, such as the IDH1/2 mutation status (codon 132 of IDH1 and codon 172 of IDH2), can help distinguish between different types of gliomas. IDH1/2 wild-type and mutant gliomas have different prognoses and treatment options, with patients with IDH1/2 mutations typically having a better prognosis and a better response to chemotherapy. However, current available molecular tests for IDH1/2 mutation detection have limited sensitivity, and their application to circulating cell-free DNA has not been well established. Methods: To address these challenges, we have developed a new technology that uses xenonucleic acids (XNA) to achieve high sensitivity and specificity for detecting IDH1/2 mutations. We designed and synthesized a specific XNA probe to block PCR amplification from the IDH1 wild-type allele so that the IDH1 mutant allele can be enriched by Taqman real-time PCR. Results: Our tests showed that the XNA-mediated Taqman Real-time PCR system could efficiently detect IDH1-R132H mutations at a frequency as low as 0.1% (e.g., 7 IDH1-R132H copies out of 7,425 IDH1 copies) in both synthetic DNA fragments and genomic DNA from glioma stem cell lines. Clinical verification and validation studies are ongoing using tissue biopsies and paired plasma circulating cell-free DNA (cfDNA). The results of these studies will further demonstrate the reliability and accuracy of our XNA-based detection technology and its potential impact on patient outcomes. Conclusions: Our innovative technology holds the potential to significantly enhance the diagnosis of gliomas and other cancers. It offers a cost-effective, readily available, and precise diagnostic solution that can be performed by standard pathology personnel using equipment already available in hospital pathology laboratories. We will showcase the innovative capabilities of our XNA-based detection technology and its potential to improve the diagnosis and management of gliomas.
Real world clinical outcomes of patients with HER2 positive metastatic breast cancer with central nervous system involvement treated with modern regimens.
Authors: Nava Siegelmann-Danieli, Idit Livnat, Roni Ginsburg, Adva Yarden, Lior Apter, Michal Drori, Anat Drizon, Gabriel Chodick, Sarah Sharman Moser
Journal: Journal of Clinical Oncology (2023)

e13040 Background: In 25-55% of Human epidermal growth factor receptor type 2 (HER2+) metastatic breast cancer (MBC) patients, central nervous system metastases will occur. Herein we describe treatment patterns and clinical outcomes in a modern series of patients with HER2+ MBC with brain metastases in a population based cohort of Maccabi Healthcare Services in Israel. Methods: Patients aged ≥18 years, who initiated first-line treatment for metastatic HER2 positive breast cancer between 1 st January 2013 until 30 th June 2021 and received brain surgery and/or irradiation were identified and followed until December 2021. The index date was fixed as the first day of first-line treatment. Time on treatment (ToT, as a surrogate for progression-free survival) and overall survival (OS) were determined. Results: A total of 61 patients with HER2+ MBC and brain metastases were identified. Median theoretical follow-up time was 6.2 years. The cohort consisted of 98.4% females, median age 50 years (IQR: 44-63), tumors were invasive ductal in 85% and in 57% were hormone receptor positive; ECOG performance status was 0-1 in 51% and missing in 32%. All patients initiated tratuzumab-pertuzumab-chemotherapy (TPC) combination, and second-line treatment was started in 72% during study follow up. Median ToT for first and second-line treatments were 16.9 months (95% CI: 13.9-27.7) and 7.92 months (5.6-10.9), respectively. In 15 patients (25%) brain metastases were diagnosed prior to TPC or within 6 months of treatment initiation, in 25 patients (41%) while on TPC treatment, and in 21 (34%) at later periods. Median OS was 45.5 months (35.4-71.2) from initiation of first-line treatment, and 36.3 months when brain metastases occurred upfront, 59.1 months when diagnosed while on TPC, and 40.8 months when diagnosed later. Median OS from brain metastases diagnosis was 25.1 months (17.0-34.6). Conclusions: We provide ToT (as surrogate for PFS) and OS on HER2+ MBC patients with brain metastases treated with upfront TPC in first line setting and mostly TDM1 in second line setting in a real-world setting. Outcome with newer anti-HER2 directed regimens for patients with brain metastases should consider clinical findings in this relatively modern series. [Table: see text]
Effect of DUAL pharmacological blockade of AURKA and PD-L1 pathways on plasticity and metastasis for triple negative breast cancer.
Authors: Andrew Takchi, Tufia C. Haddad
Journal: Journal of Clinical Oncology (2023)

e13100 Background: Aurora-A mitotic kinase (AURKA) plays a pivotal role in Triple Negative Breast Cancer (TNBC) progression through activation of epithelial to mesenchymal transition (EMT)-mediated cancer cell plasticity. Cancer cells that undergo EMT acquire a CD44 high /CD24 low and/or ALDH high cancer stem-like phenotype (Cancer Stem Cells) characterized by high self-renewal capacity and intrinsic drug resistance. Cancer Stem Cells (CSCs) also shows high PD-L1 expression that plays a critical role in inducing tumor immune escape through CD8+ T-cells exhaustion. For these reasons, molecular characterization of oncogenic pathways that promote stemness and intra-tumoral PD-L1 expression is essential to evaluate whether novel combinatorial therapeutic strategies aimed to inhibit cancer cell plasticity, immune evasion capacity and organ metastasis may impact cancer progression. Methods: (1) TNBC Models: MDA-MB 231 and variant MDA-MB 231/LM cells, and unique TNBC-M40 cells established from metastatic PDXs; (2) In Vitro Studies: TNBC cells were treated with the AURKA inhibitor alisertib (50nM). PD-L1 expression was evaluated by immunoblotting assay. Apoptosis was measured by immunofluorescence using Cleaved-PARP antibodies. To assess stemness capacity, TNBC cells were cultured under non-adherent conditions to form mammospheres. ALDH activity (functional stemness marker) was measured using the Aldefluor Kit. (3) In Vivo Studies: 1x10 6 MDA-MB 231/LM cells were injected into the mammary fat pad of humanized NSG-CD34+ female mice. Animals were randomized into four groups (5 mice per group) and treated with anti-PD-L1 ICI atezolizumab (20 mg/Kg) and alisertib (25 mg/Kg) as monotherapy or in combination. Control groups were treated with saline solution placebo. PD-L1, CD44, Vimentin expression and tumor infiltration of CD8+ T-cells were assessed by immunofluorescence. Results: Treatment of MDA-MB 231/LM xenografts with alisertib decreased the levels of CD44 and PD-L1 expression and increased CD8+ T-cells tumor infiltration. Because PD-L1 genetic targeting enhanced in vitro alisertib-induced apoptosis, MDA-MB 231/LM xenografts were treated with alisertib and the anti-PD-L1 ICI atezolizumab. Combination of atezolizumab and alisertib resulted in the reduced expression of the EMT marker vimentin that was linked to lack of organ metastasis. Remarkably, combination of atezolizumab and alisertib also induced a significant reduction of ALDH High CSC in ex-vivo 3D-Organoids established from TNBC-M40 cells. Conclusions: This study provides innovative pre-clinical rationale for combining AURKA inhibitors with ICIs to impair cancer cell plasticity, immune evasion capacity and halt the progression of metastatic TNBCs that currently has limited effective therapeutic options.
In search for new targets: Differences of HER2 receptor expression between CNB and synchronous axillary lymph node metastases in 205 patients.
Authors: Laura Weydandt, Senol Dogan, Ivonne Nel, Lars-Christian Horn, Bahriye Aktas
Journal: Journal of Clinical Oncology (2023)

e12559 Background: Lately large clinical trials have provided new treatment options for patients with metastatic HER2-low breast cancer. Studies have shown that there may be change in the expression of HER2 during disease progression. Yet, it is rarely considered that there can be already differences between primary tumor and synchronous lymph node metastases (LMN) in the primary setting. The aim of the present study was to analyze different HER2 expression profiles between primary tumor and synchronous LNM. Methods: We included 205 patients with primary breast cancer and LNM who underwent oncologic surgery between 2008 and 2021. Formalin-fixed and paraffin-embedded (FFPE) material were routinely examined immunohistochemically according to the ASCO guidelines. Membranous HER2-staining was scored as follows: zero = 0, low = 1+, equivocal = 2+ and positive = 3+. Results: 205 patients were either HER2 low or HER2 zero in CNB. When comparing CNB and LNM 5 (2,4%) patients were HER2 zero in CNB and HER2 low in LNM. 161 (78.5%) patients were HER2 zero in both CNB and LNM. 21 (10.2%) patients had a shift from HER2 low to HER2 zero in LNM. 18 (8,8%) patients had a HER2 low expression in CNB and HER2 zero expression in LNM. Conclusions: There seems to be a high frequency of HER2 heterogeneity between primary tumor and LNM in the primary setting. Different HER2 expression profiles should be considered for an optimal and individual treatment.
Treatment pattern of early-stage premenopausal breast cancer patients with low Oncotype DX score: Single center experience.
Authors: Zaid Ihab Al Saheli, Omar Ammari, Linda Albusoul, Vrushali S. Dabak
Journal: Journal of Clinical Oncology (2023)

e12510 Background: The predictive value of Oncotype DX in early-stage node negative breast cancer had been previously well established. As per TAILORx, patients with a low Oncotype DX Recurrence Score RS (0–25) did not benefit from chemotherapy. Premenopausal patients are a crucial subgroup for which recommendations based on Oncotype DX are imprecise. Those with Oncotype DX RS 16-25 are thought to have a small benefit from chemotherapy. Our goal was to study the treatment pattern for this group of patients managed at our institution. Methods: We conducted a retrospective analysis to assess premenopausal patients with early-stage breast cancer who had Oncotype DX testing done. All eligible patients were compared based on whether chemotherapy was given or not. The primary endpoint evaluated was the rate of local recurrence. Univariate comparisons were assessed using t-tests or ANOVA for continuous variable &amp; chi-square for categorical variable. Results: A total of 506 patients younger than 50 years diagnosed between 01/2018 and 12/2020 who had an Oncotype DX available were identified. Of these, 344 were White, 137 were Black and 23 identified as another race. The average age of patients was 42.7 ± 5.5 years. Patients treated with chemotherapy were found to be on average younger than those who did not receive chemotherapy (42 years old vs 43.6 years old, P &lt; 0.0001). The average tumor size for patients who got chemotherapy was 3.26 cm compared to an average size of 2.78 cm for patients who avoided chemotherapy. 72.1% of patients with stage 2 disease had received chemotherapy compared to 38.1 % of patient with stage 1. There were 462 patients with RS &lt; 16, 28 patients with RS 16-25, and 16 patients with RS &gt; 25 as illustrated. Patients were followed from a range of 1.8 months to 30.7 months. There were 6 patients who had local recurrences identified, all of which had RS scores &lt; 16. Conclusions: In our study, 91.3% had RS &lt; 16 and generally should have avoided chemotherapy, however 35% of these patients continued to receive chemotherapy. Only 5.5% of our population had RS 16-25, a quarter of which (n = 7) received chemotherapy. Of those 7 patients, 3 had positive lymph node disease. None of these patients had disease recurrence to date. Patients with RS &gt;25 made up 3.2% of the population and would generally benefit from chemotherapy, however 12.5% of these patients did not end up receiving it. Using Oncotype DX in early-stage breast cancer helps avoid chemotherapy safely in majority of patients. [Table: see text]
Racial/ethnic and socioeconomic differences in breast cancer surgery performed and delayed surgical treatment: Mediating impact on mortality.
Authors: Ayrton Bangolo, Pierre Fwelo, Kenechukwu O.S. Nwosu, Toluwani E. Adekunle, Oladipo Afolayan, Onyekachi Ahaiwe, Akpevwe A. Ojaruega, Vignesh Nagesh, Amer Jarri, Shraboni Dey, Angel Ann Chacko, Bhavna Gupta, Adam Atoot
Journal: Journal of Clinical Oncology (2023)

585 Background: Breast cancer is the most common malignancy affecting women of all racial and ethnic backgrounds in the United States (US). Although Socioeconomic status (SES), race/ethnicity, and surgical type/delays are associated with breast cancer mortality outcomes, studies on these associations have been contrasting. This study examined the racial/ethnic and SES differences in surgical treatment types and delays. Also, we quantified the extent to which these differences explained the racial/ethnic disparities in breast cancer mortality. Methods: We studied 290,066 women 40+ years old diagnosed with breast cancer between 2010 and 2017 identified from the Surveillance, Epidemiology, and End Results database. We performed logistic regression models to examine the association of SES and race/ethnicity with surgical treatment type and delays. We performed mediation analysis models to quantify the extent to which mortality differences were mediated by treatment, sociodemographic, and clinicopathologic factors. The study subjects were de-identified, and there was no patient contact; thus, the study was exempted from an Institutional Review Board's (IRB) approval. A p-value less than 0.05 indicated significant associations for the descriptive statistics, logistic and Cox proportional hazard regressions, and mediation analysis. We used Stata 17 to perform the analyses. Results: Non-Hispanic (NH) Black [Odds ratio (OR) = 1.16, 95% CI: 1.13-1.19] and Hispanic women [OR = 1.27, 95% CI: 1.24-1.31] were significantly more likely to undergo mastectomy compared to NH White women. Similarly, NH Black and Hispanic women had higher odds of delayed surgical treatment than NH Whites. Patients in the highest SES quintile, compared to those in lowest the lowest, were less likely to experience breast cancer-specific mortality (BCSM). Variations in treatment, SES, and clinicopathological factors significantly explained 70% of the excess BCSM among NH Blacks compared to their NH White counterparts. Conclusions: In conclusion, health disparity continues to be a major societal concern in the US. It affects people of all ages, socioeconomic classes, and ethnic/racial backgrounds. The findings of this study showed that racial and ethnic minorities, the majority of whom have a lower socioeconomic position, are significantly disadvantaged regarding the evaluation, quality, cost, and duration of medical care. Future studies can assess the multifactorial effects of sociodemographic factors like SES, access to health care assessment, and educational background amidst other variables as a multidimensional predictor of treatment delay and overall survival of breast cancer and other health issues among minoritized populations.
Association between baseline radiological tumor burden and outcomes in patients with metastatic breast cancer treated with an immune checkpoint inhibitor.
Authors: Lauren Claire Brown, Kate Moodie, Courtney VanGeelen, Julia Dixon-Douglas, Steven Philip David, Prudence A. Francis, Peter Savas, Sherene Loi
Journal: Journal of Clinical Oncology (2023)

1103 Background: Lower baseline radiological tumor burden is associated with more favorable outcomes for patients with metastatic non-small cell lung cancer and melanoma treated with immunotherapy. However, minimal data is available for metastatic breast cancer patients. This is despite immunotherapy, in combination with chemotherapy, now being standard-of-care for a subset of metastatic breast cancer patients who have triple-negative disease and are PD-L1 positive. Methods: We reviewed data of 82 patients with metastatic breast cancer consecutively treated at our institution from August 2015 to October 2021, who received &gt; 1 dose of an immune checkpoint inhibitor (anti-PD-1 or -PD-L1) within the context of a clinical trial. Baseline tumour burden was assessed by a single radiologist and calculated as sum of Response Evaluation Criteria in Solid Tumours 1.1 baseline target lesions (baseline tumour size [BTS]) or as sum of all measurable baseline lesions (total tumour burden [TTB]); the impact of both parameters on treatment outcomes was investigated. Treatment outcomes assessed were clinical benefit rate (complete response, partial response or stable disease for 6 months or more [CBR6]), disease free survival (DFS) and overall survival (OS). Multivariate analysis adjusted for ECOG status, line of treatment (first line vs second line or beyond), and whether immunotherapy was given in combination with chemotherapy or as monotherapy. Results: A total of 82 patients were included in the analysis. 43 patients (52%) received combination chemotherapy with immunotherapy, 39 patients (48%) received immune checkpoint inhibitor monotherapy. Median BTS and TTB were 36.5mm (range 0 -204mm) and 43mm (range 0 – 1123mm) respectively. CBR6 was significantly associated with BTS (p=0.004) and TTB (P=0.002) quartiles, with clinical benefit time progressively increasing with decreasing tumor burden quartiles. Both increasing BTS (p&lt;0.001) and TTB (p&lt;0.001) across quartiles were significantly associated with shorter OS. There was a numerical, but not statistically significant, association between both parameters as quartiles (BTS, p=0.25; TTB, p=0.07) and PFS. In the bottom BTS quartile, 32% of patients were progression-free and 95% alive at 12 months, compared with 15% and 40% respectively in the top quartile. Similar results were seen when TTB was used as the baseline measurement: 32% progression-free and 95% alive at 12 months in the bottom quartile compared with 1% and 33% in the top quartile. Multivariate analysis confirmed that both BTS and TTB, considered as continuous variables, are independently associated with OS. Conclusions: Lower baseline radiological tumor burden is associated with better outcomes in patients with metastatic breast cancer treated with immune checkpoint inhibitors.
Implementation of a streamlined prior authorization process to improve cancer care delivery.
Authors: Aarti Sonia Bhardwaj, Mark Liu, Sofya Pintova, Chanda Williams, Jennifer Liggins, Haydee Soto, Daniel Favre, Alana Noble-Kirk, Cardinale B. Smith
Journal: Journal of Clinical Oncology (2023)

1531 Background: Prior authorizations (PAs) for systemic cancer treatments are increasingly becoming a barrier to timely quality cancer care delivery. There is an extraordinary administrative burden placed on clinicians to complete peer to peers (P2P) and appeals when authorization specialists are unable to identify appropriate clinical data in the EHRs. This leads to delays in care, staff burnout and loss of revenue. At our tertiary academic cancer center, in partnership with our cancer registry and Epic teams, we propose shifting the clerical work required for intravenous chemotherapy PAs from clinicians to certified tumor registrars (CTRs) to improve documentation needed for authorization specialists and decrease PA associated clinician burnout. Methods: Clinicians first place the treatment plan order which goes to the CTR work queue. We leveraged the Epic staging smart form to consolidate and auto-populate a list of common data elements needed for PA (performance status, cancer biomarkers, stage, line of treatment, and goals of treatment). The CTRs then complete and validate all elements necessary for authorization specialists to obtain the PA. Our primary outcomes include: average monthly number of intravenous chemotherapy authorizations pending review (including P2P, appeals and authorizations requiring other clinical interventions from the primary team) during a pre (9/1/2021-9/30/22) and post-implementation (11/14/22-1/30/23) period. Analyses were conducted using descriptive statistics. Results: The average monthly number of authorizations pending review was 332 pre-implementation and 227 post-implementation, which is a 32% reduction. To account for temporal changes, when comparing December 2021 to January 2022 vs December 2022 and January 2023, the average number of referrals pending review was 276 vs 227 which is an 18% reduction. First line treatment regimens accounted for most regimens requiring review; 28% and 27% pre-implementation and post-implementation, respectively. Non-chemotherapeutics like lanreotide and feraheme had the highest pending review status pre-and post-implementation respectively. Among chemo/immunotherapeutics, Nivolumab and Trastuzumab deruxtecan had the highest pending review status pre and post implementation, respectively. GI regimens had the highest number of regimens requiring review accounting for 17% vs 22% of all referrals pre and post implementation, respectively. Conclusions: By leveraging technology and increasing efficiencies of existing non-clinical staff workflows, we significantly decreased the number of ambulatory chemotherapy PAs that required further clinical review including P2P and appeals thereby improving efficient care delivery. Next steps include evaluation of sustained improvement, time to final authorization, revenue analysis and the impact on the well-being of clinicians.